Addiction and posttraumatic stress disorder (PTSD) have been proposed to share a common mechanistic basis. A fundamental characteristic of both disorders is impaired activity of the prefrontal cortex, which may exist prior to disease onset and lead to a delay in the extinction of Pavlovian conditioning. Understanding the molecular basis of prefrontal cortex function may uncover drug targets for the treatment and prevention of these disorders. We have data showing that mice lacking an intracellular signaling enzyme, protein kinase C-epsilon (PKC5), exhibit behavioral signs of impaired prefrontal cortex function in models of PTSD, addiction and behavioral flexibility. These data suggest that signaling through PKC5 is necessary for normal functioning of the prefrontal cortex. In a separate project, funded by the US Department of Defense, we are using RNA-interference to identify the anatomical site of action for PKC5 in the extinction of conditioned fear as well as testing PKC5 activators to determine if they can accelerate the extinction of conditioned fear. Currently the anatomical substrates that mediate the extinction of conditioned drug seeking are poorly understood. In this proposal we will identify the neuroanatomical regions that mediate the extinction of conditioned drug seeking using lesion studies. We will also determine whether enhancing the acquisition process leads to a delay in extinction. SPECIFIC AIM ONE Extinction of a drug conditioned place preference is mediated by the infralimbic cortex We will lesion the infralimbic or entire medial prefrontal cortex of mice and then examine the extinction of a conditioned place preference for cocaine, morphine and ethanol. SPECIFIC AIM TWO PKC5 null mice show delayed extinction of a conditioned place preference for cocaine and amphetamine. Our current data demonstrate that PKC5 mull mice exhibit delayed extinction to a conditioned place preference for morphine and ethanol. To confirm that this extinction delay generalizes to other drugs of abuse, we will examine the extinction of a conditioned place preference for both cocaine and amphetamine. SPECIFIC AIM THREE PKC5 null mice show enhanced acquisition of conditioned discrimination. We have shown that PKC5 null mice exhibit a delay in the extinction of Pavlovian conditioning. It is possible that this delay arises through an "enhanced acquisition" process, whereby PKC5 null animals are better able to discriminate between correct and incorrect choices, or display greater attention to the correct choice. We will measure the acquisition of a Pavlovian conditioned discrimination task. PUBLIC HEALTH RELEVANCE: Drug addiction and posttraumatic stress disorder (PTSD) are debilitating conditions that often occur together, suggesting that they share a common biological basis. This hypothesis is supported by epidemiological, behavioral and functional imaging studies. A common theme of these studies is that patients have impaired function of a part of their brain called the prefrontal cortex. This brain region controls motivation and drive, as well as facilitating the ability to forget learned associations (for example, fearful memories or associations between drugs and the location in which they were taken). We have data showing that mice lacking an intracellular signaling enzyme, protein kinase C-epsilon (PKC5), exhibit behavioral signs of impaired prefrontal cortex function in models of PTSD, addiction and behavioral flexibility. We are currently funded by the US Department of Defense to determine where in the brain PKCe acts to control behavior in a mouse model of PTSD. In the current proposal, we will lay the foundations for proposals to determine the brain regions in which PKC5 acts to control addictive behavior.